The cause of multiple sclerosis (MS or encephalomyelitis disseminata) is unknown and the pathogenic processes leading to disease development are incompletely understood. Current knowledge supports a T cell mediated autoimmune pathogenesis targeting myelin components or myelin-producing cells. MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are characterized by the activation and accumulation of antigen presenting cells (APCs) and auto-reactive lymphocytes within the central nervous system (CNS). Some of the myelin proteins known to be recognized by self-reactive T cells include myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG).
Myelin basic protein (MBP) is a major constituent of the myelin sheath of oligodendrocytes and Schwann cells. The genetic data of its human orthologue are published under gene ID 4155 at the US National Centre for Biotechnology Information (NCBI); the human MBP protein data can be accessed at UniProt under P02686.
Proteolipid protein (PLP; lipophilin) is the major myelin protein from the central nervous system. It plays an important role in the formation or maintenance of the multilamellar structure of myelin. The genetic data of its human orthologue are published under NCBI gene ID 5354; the human MBP protein data can be accessed at UniProt under P60201.
Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein believed to play a role in providing structural integrity to the myelin sheath. The genetic data of its human orthologue are published under NCBI gene ID 4340; the human MBP protein data can be accessed at UniProt under Q16653.
The etiology of multiple sclerosis is not yet completely understood and there is no curative treatment available at present. Autologous, T cell depleted bone marrow transplantation has been shown to be effective and beneficial in clinical trials on multiple sclerosis patients. However, disease relapse due to re-emergence of auto-reactive T cells suggests that specific treatment should consider the induction of permanent immune tolerance. Dynamic changes in the anti-myelin T-cell reactivity pattern (antigen spreading) that have been demonstrated in several studies, however, as well as the difficulty in safely inducing tolerance via altered peptide ligand-based treatment, have raised questions about the usefulness of the current strategies for antigen-specific immunotherapy of multiple sclerosis.
The standard treatment of autoimmune diseases relies on generalized immune-suppression. However, even with the difficulties described above, it is important to design novel antigen-specific forms of therapy, which conserve the ability of the immune system to combat pathogens and cancer. For example, previous studies have shown that bone marrow derived HSC transduced with standard gamma retrovirus vectors expressing MOG or PLP can protect mice from EAE. These investigators used constitutive promoters that can mediate MOG expression in different hematopoietic cells, which may cause adverse side effects. To overcome this limitation, Ko et al. have used the cd11c promoter in the context of standard gamma retrovirus vectors to direct MOG expression to dendritic cells (DCs). Although this strategy delayed disease onset, it did not prevent EAE development (Ko et al., 2010, Eur. J. Immunol. 40, 3499-3509).
Dresch et al. (J. Immunology 2008, 181; 4495-4506) demonstrated that transduction of hematopoietic stem cells (HSC) with self-inactivating (SIN) lentivirus vectors that express EGFP or ovalbumin (OVA) from the DC-specific DC-STAMP promoter results in the transcriptional targeting of transgene expression to DCs and in the antigen specific induction of immune tolerance.
The objective of the present invention is to provide means and methods to allow induction of tolerance to autoantigen reactive immune processes in MS, thus reversing the established autoimmune process, alleviating the symptoms and halting the progress of multiple sclerosis.